iwNHL 2025 | Mantle cell lymphoma: frontline therapy, the role of autoSCT, the value of MRD, & more

Stephen Ansell:

Hello, my name is Steve Ansell. I’m from Mayo Clinic. I’m joined by two of my colleagues, Dr Michael Wang from MD Anderson, Dr Tycel Phillips from City of Hope. We’re going to talk about a really interesting session on mantle cell lymphoma that we’ve just had at the iwNHL meeting. And this is a very dynamic field, lots of interesting conversations. So I’m really going to appreciate and enjoy the comments from my colleagues on this really important field. So starting out, we once had a pretty robust conversation about frontline treatments and how things are changing. And Michael, I’m going to ask you to start off. A lot of things have changed in how we manage mantle cell lymphoma in the frontline. Would you like to tell us about what you feel are the major changes that have happened maybe within the last three to five years? 

Michael Wang:

Okay, Dr Ansell, thank you for that very good question. So I really think that first of all, we have learned from all our data and we have a philosophical change in that we recognize the first therapy for the mantle cell lymphoma patients is the most important therapy and is the point that is the best opportunity to cure the patient. And mantle cell lymphoma is such a disease that the first treatment is very effective, most effective. The second one, the response is not as good. The more lines of therapy, the less the efficacy. And second of all, the front line therapy for the patients who have never been exposed to any therapy, the body reserve is still there. The patient’s financial, social support is still there. And so the best frontline, the first therapy for mantle cell lymphoma is most important. And also we recognize that mantle cell lymphoma is a disease of older people. Therefore sometimes the older people also have infections, they have cardiac diseases, and if they get the treatment of mantle cell lymphoma, 25% of the time they don’t have a chance for the next treatment. So that makes the first therapy so important. The major change since the past many years, Steve, that we have learned that we don’t have to use chemotherapy anymore. We are using chemo-free therapies. For example, we have chemo-free combinations with a BTK inhibitor, we have a BCL-2 inhibitor, and we have also the CD20 monoclonal antibody. This framework has been tested by different institutions, and some tested in the TP53-mutated patients, and those have so far showed high responses over 90% and CR around 90%. So those data, we hope that we have a longer follow-up with data, but so far, a lot of major academic centers are using totally chemo-free therapies. That was one of the main changes. 

Stephen Ansell:

So I think you’ve made a number of points, which I want to break down a little bit more. So Tycel, I’m going to bring you in here. The whole thinking in the past was young = fit, old = frail, and having a different approach. Do you think that approach is done? 

Tycel Phillips:

As of right now, we still have that bit of a dichotomy. I mean, I think, as Dr Wang has sort of discussed, as we move along, the hope is that the treatments that we’re using in a frontline space will sort of mitigate some of the risks that we have with older patients, meaning the treatments won’t cause as much sort of physical decline in the patients, which will allow us to treat older patients just as well as we’re treating patients who we consider to be fit or those who are quote unquote young. But I think again, there’s always some question about how everybody as we start adding more and more treatments, how this will sort of impact patients. So far so good with these multiple targeted treatment regimens. It seems to be that they are agnostic to age, which is an encouraging sign. I just think as we move along, we just need more data discussing the durability of those responses and see if we can finally put the rest sort of the young old fit unfit sort of dichotomy that we have. 

Stephen Ansell:

And I also want to ask you a follow-up question. So Michael made a great comment about, well, we’re moving to chemo-free. But I guess the question is, are we? Because many people in the real world, bendamustine plus rituximab is kind of their go-to regimen. Maybe or maybe not, they add a BTK inhibitor. What do you think about chemo-free versus not? And what do you think about standard drugs like BR on its own, maybe with maintenance, just maintenance rituximab versus a BTK mixed in? 

Tycel Phillips:

Yeah, I think the last question is a bit easier. I think we have years of data and support there. For most patients, bendamustine-rituximab has quite a significant durability of response, and even in older patients, I think it’s shown to be quite tolerable. There is old data from the cooperative group that showed even in younger patients, you can probably get a very decent and durable response with bendamustine. Even though the trial didn’t complete enrollment, it appeared to be quite comparable to hyper-CVAD in younger patients. That being said, as we sort of discuss whether chemo is something that’s on the way out and these sort of non-chemo[unintelligible], I think it depends on who you ask. I think in academic centers, we are wholeheartedly trying to move away from chemotherapy, but that’s because, you know, obviously we have a little bit more experience with these other drugs and obviously we have more options to offer our patients. Whereas in the community, I think where the vast majority of patients are treated, I don’t think chemotherapy has gone away. I think regimens… they’re just more so looking to add to what they’re more comfortable with. And so the question is whether we’ll ever really get rid of bendamustine, that’s probably not likely to happen in the short term, because again, I think with the advent of the ECHO study, it just gives more reason for community physicians to still use bendamustine just by adding the BTK inhibitor. Now, whether that’s needed or not, I don’t think they necessarily going to look into the weeds. Whereas I think there’s data that has even come out of Mayo to suggest that you probably can split these drugs up and get a fairly equivalent sort of duration of response. But in the community, again, you’re treating multiple different diseases. I don’t think that’s necessarily going to come to the forefront versus acal is something they can tolerate, we have experience with that, and BR is something we’ve used for quite a bit of time. So why not give the drugs together and not think about sort of what’s next in this situation? 

Stephen Ansell:

Right. Michael, to come to you, talking about things we’re getting rid of. So the other big discussion is about, is an autologous stem cell transplant as a consolidation – are we done with that? So maybe if you want to give us a little bit of your perspective of what does the data show? And then in your practice, do you use autologous transplant, yes or no? 

Michael Wang:

So I, first of all, I do not use autologous stem cell transplant. The nature of autologous stem cell transplant is a high-dose chemotherapy, such a high-dose that you have to rescue the patient back, using the patient’s own stem cells preserved before you deliver the high-dose chemotherapy. So autologous stem cell transplant in nature is the highest-dose chemotherapy a human can get with the stem cell support. Then at MD Anderson, we had a hyper-CVAD. We didn’t use autologous stem cell transfer for many years with hyper-CVAD. But hyper-CVAD, eight cycles, basically is the highest chemotherapy you can give to a human without the stem cell transplant. So all these high dose chemotherapies, the patients wear a big catheter, they lose their hair, they look pale, they oftentimes have to stay in the hospital. The cell counts are so low at the later point, they all have transfusions. Some people get neutropenic fevers and some people, 2% of people, don’t even make it alive after the chemotherapy. So the most important point that I talked to is acute toxicity. Also gram-negative sepsis, also acute toxicity. But the later toxicity is secondary malignancies, including MDS, leukemia, and solid tumors. I really think that… and I also think that chemotherapy induced secondary cancers are underreported and underestimated. And therefore, I really think moving away from chemotherapy is very, very important. And we are making headlines. We’re using three chemo-free therapies together. And I think in the future, we probably need four or five agents designed in the clinical trial that we do not give them concurrently as at the same time, they will bring a lot of toxicity. We designed it in an intelligent way. We use induction, we use consolidation, and we use maintenance. This way, we can use five targets, attack the target, addressing the heterogeneity. I think we will achieve, it is my belief, eventually, we will use totally chemo-free therapy to beat the intensive therapies. 

Stephen Ansell:

So just picking up on the transplant moving away, moving to other novel agents. Tycel I wanted to ask you, so one of the studies that showed the lack of benefit to an autologous transplant used MRD after initial treatment as a way to determine whether to do a transplant or not, and that was where the randomized comparison was. What’s your view of MRD? Because again, I think the challenge for some is if you were never going to do a transplant, who cares about MRD? And so just… do you use it in your practice? How do you see it being valuable or is it valuable? 

Tycel Phillips:

Yeah, I think for the longest we’ve been trying to figure out the best way to incorporate minimal residual disease. And I do think it’s useful. I think we have a ton of data that’s come out of Germany, different assay than what we have in the United States that’s suggesting that MRD is probably a better predictive of long-term remission versus what we use with conventional radiographic imaging. I’ll bet a lot of that was with CT scans and not with PET scans, but to the point of the E14151, I mean, again, it suggested that, again, you could avoid autologous stem cell transplantation in those who are MRD undetectable. And that was a big sort of pragmatic shift because we were outside of other… most institutions were still using transplant quite a bit. And that has allowed us to have some confidence in saying that, again, if you can get an MRD undetectable assay in these patients, more than comfortable just to use a rituximab maintenance and avoid the toxicity that comes with stem cell transplantation. I think as we move forward, I think some of the key caveats will be, can we actually use this MRD assay in a more sort of predictive and actionable way where if the patient is MRD-positive, can we actually intervene before the patient has a clinical relapse and sort of prolong these remissions that we have for our patients and avoid undue toxicity from having to go through a second induction. That would be the ideal method if we could in the future. Now, as far as my clinical practice, now that it is something we can readily get reimbursed for the most part from insurances, we are actually adding it to most of our patients once they start an induction therapy. We’re using it in a sense, ideally, just to provide some sort of assurance and confidence to the patient that at least with induction, we’ve got them to at least a deep response, and the hope is that with maintenance, we can maintain that response to provide some durability. And in some situations, I mean, a lot of times they, again, refer to our center. We’re sort of using these as guides to sort of determine whether we need to add extra agents or not in the maintenance setting. A bit of a, not necessarily really a study, but again, we’re trying to figure out ways we can utilize this assay in a more useful manner just to say you’re undetectable, and we hope that your remission remains durable versus, yeah, it’s detected or positive, and so maybe there’s something more we can do to hopefully keep you in a long-term remission. 

Stephen Ansell:

Right. So, Michael, I wanted to ask you a question. You said five drugs, four or five drugs altogether. So the question is altogether or sequential? So could we not, should we not be stringing out these drugs one after another, or do we really want to just dump them all together and go with just one approach with everything? 

Michael Wang:

For example, I think using two agents to induce a response in all agents like a BTK inhibitor, a monoclonal antibody, and use such as a bispecific antibody, you know, the highest risk is maybe a cell therapy as a consolidation, and then followed by a triple drug maintenance for two years. This way, we use four to five drugs, but they’re not used altogether, but they are used as one line on therapy. So I think that will really push the complete remission rate beyond 12 years. I did a WINDOW-1 study treated 131 patients published in the Lancet Oncology. We are collecting the longer term follow-up data. So many, many patients have reached 10 years complete remission, without any interruption. I feel if the patient has a CR that’s more than 15 years without any interruption, that’s a mini cure of clinical parameters. So I really think we are making strides in mantle cell lymphoma. We are in the process of curing some of the patients with mantle cell lymphoma. 

Stephen Ansell:

So I think good point. So it’s sort of of a hybrid approach in that it’s one phase of treatment, but it isn’t necessarily all the drugs together, it’s broken up a little bit. So, Tycel, the last question I think for you is just, there are data, and you presented this very nicely, where if you put the one drug after the other, the results are not as good. So, to the whole thing of how you mix it, how would you recommend mixing the regimens? 

Tycel Phillips:

Yeah, I mean, I think what we see is, which I wish we had a very clear picture, BTK inhibitors have changed the tumor because the disease itself is more responsive to agents when they’ve never seen a BTK inhibitor. Once they’ve unfortunately progressed on this drug, the responses to agents that are after that seem to be quite less. So, I mean, we look across the IMiDs, BCL2 inhibitors, PI3 kinase inhibitors. We’ve studied all of them, and they all unfortunately don’t have durability of response. So, as of right now, it seems like Venetoclax, the BCL2 inhibitor, is a great partner with the BTK inhibitor. So I do think as we are looking at these other small molecules, how to pair them toxicity-wise and efficacy-wise, it seems like that is the best partner for the BTK inhibitors, allows us to maximize the BCL2 inhibitor and then obviously not have as much toxicity as we see when we use IMiDs or when we use the PI3 kinase inhibitors. You know, as we move forward, I think that there may be other drugs that pair better with the BTK inhibitor or may not necessarily be impacted as negatively after a BTK inhibitor, such as those T-cell directed therapies. So again, as we get more data in the future, that may help us better sort of sequence these drugs a bit better, or maybe alter the sequence based on how some of the data sets come out. 

Stephen Ansell:

Well, with that, I’d like to thank Dr Wang, Dr Phillips for their insights and their comments and thank you for watching this program. Thank you. 

Michael Wang:

And Dr Ansell, we thank you as well. 

Tycel Phillips:

Thank you.

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